DESCRIPTION, OVERALL (provided by applicant): The Columbia University George M. O'Brien Urology Cooperative Research Center brings together an experienced group of investigators with a long track record of productive collaboration to address a major problem in benign urology. Vesicoureteral reflux, posterior urethral valves and related forms of urinary tract obstruction are common birth defects in humans and account for 20% chronic kidney failure in children. Kidney damage can be due to intrinsic genetic abnormalities that impair both nephrogenesis and ureteric function, or may be linked to scarring associated with recurrent febrile UTIs. This Center will employ a multidisciplinary approach to address the origins of development defects and their complications in humans and mouse models. The Center consists of 3 research projects, 2 pilot projects and an administrative core. Project 1 will undertake a comprehensive genomics approach to elucidate the pathogenesis of VUR in humans by examining the interplay between common and rare variants that can be discovered by GWAS, CNV analysis and exome sequencing approaches. Project 2 will study the role of the urogenital sinus in the genesis of posterior urethral valves and obstruction using mouse mutants lacking Sall1 and RA-signaling, both of which display obstruction. Project 3 will examine the interaction between structural defects and antimicrobial proteins secreted by the alpha-intercalated cells in the development of urinary tract infections and kidney injury. These projects are complemented by innovative pilot proposals that aim to discover rare mutations by exome sequencing in human cohorts posterior urethral valves (Pilot 1) and map loci predisposing to urinary tract infection by performing a GWAS in inbred mouse strains. (Pilot 2). The scientific aims of each these projects are highly interconnected, and will require vigorous exchange of ideas, seamless data sharing and multidisciplinary, collaborative efforts to achieve success. Thus, a central theme of this project is to serve as a model for collaborative activity and data sharing between urology investigators and through these projects, we will develop models for dissemination of scientific findings within the urology community. Finally, our O'Brien center has a major emphasis on education of the next generation of clinician-scientists in Urologic research, with annual workshops, bimonthly seminar series, summer student training programs, and minority outreach programs. We will also use the opportunity pool mechanism to interact with the NIDDK P20 planning centers and K12 KURe centers to attract new investigators to study important problems in benign urology.